1,4,5,6-Tetrahydroimidazo[4,5-d]diazepine derivatives or salts thereof

ABSTRACT

To provide a compound having a superior arginine vasopressin antagonism. A novel 1,4,5,6-tetrahydroimidazo[4,5-d]benzazepine derivative or a pharmaceutically acceptable salt thereof.

TECHNICAL FIELD

[0001] The present invention relates to a novel1,4,5,6-tetrahydroimidzo[4,5-d]benzazepine derivative or a salt thereofuseful as a drug, especially an arginine vasopressin receptor antagonistand to a drug comprising the compound as an active ingredient.

BACKGROUND ART

[0002] Arginine vasopressin (AVP) is an antidiuretic hormone of apeptide comprising 9 amino acids as biosynthesized and secreted in ahypothalamohypophysial system and is known to have an action to promotewater reabsorption in a kidney distal uriniferous tubule, contract ablood vessel and elevate a blood pressure and to act as aneurotransmitter, etc. in a brain.

[0003] As a receptor of AVP, there are known three kinds of subtypes ofV_(1A), V_(1B) and V₂. An AVP receptor antagonist to competitivelyinhibit the binding to the V_(1A) and/or V₂ receptor of AVP is expectedas a drug for suppressing contraction of a vascular smooth muscle andsuppressing pressure rise or as a drug for suppressing waterreabsorption in a kidney collecting tubule, or as a drug having acombination of these actions (see NIPPONRINSHO, Vol. 58, Special Issue,“Hypertension (the Last Volume)”, pp. 292-296 (2000)).

[0004] On the other hand, with the diversification of medical treatmentand the age advance, it has become uncommon to use a drug singly, and inthe most case, a plurality of drugs are administered simultaneously orwhile shifting the administration time. This is also applicable in thefield of the AVP receptor antagonist. The drug is inactivated in a liverdue to the action of drug metabolizing enzymes and converted into ametabolite. Among these drug metabolizing enzymes, cytochrome P450 (CYP)is the most important. CYP includes many molecular species. When aplurality of drugs metabolized from CYP of the same molecular speciescompete on the metabolizing enzyme thereof, it is considered that thedrug receives some metabolic inhibition depending on the affinity of thedrug with CYP. As a result, drug interactions such as rise ofconcentration in blood and prolongation of half-life in blood arerevealed.

[0005] Such drug interactions are not preferred except the case wherethe drug is used with the intention of revealing an additive action orpotentiation, and there may be the case where an unexpected side effectis revealed. Accordingly it is demanded to create a drug having a lowaffinity with CYP and a little possibility of the drug interaction.

[0006] Hitherto, as the foregoing AVP receptor antagonist, compounds ofa peptide type and compounds of a non-peptide type have been synthesized(see, for example, JP-A-2-32098, WO 91/05549, EP0382185, WO 93/03013, WO95/03305, WO 95/06035, and WO 97/15556).

[0007] Among them, WO 95/03305 discloses that a condensed benzazepinederivative represented by the following general formula or its salt isuseful as an AVP receptor antagonist.

[0008] (In the formula, the symbols are as defined in the patentdocument.)

[0009] That is, this patent document describes some condensedbenzazepine derivatives and salts thereof but does not disclose at allthe compounds of the invention, wherein the ring B represents anoptionally substituted nitrogen-containing aromatic 5-membered ringhaving at least one nitrogen atom and further optionally having oneoxygen or sulfur atom; R¹ represents a hydrogen atom; A represents—NHCO—(CR³R⁴)_(n)—; n is 0; and the ring C represents an optionallysubstituted benzene ring. Further, this patent document describes the V₁and/or V₂ receptor antagonism of AVP but does not mention the inhibitionactivity against the drug metabolizing enzyme CYP.

[0010] As described previously, as the AVP receptor antagonist, thecompounds as described in the above-cited patent documents are known.But, it is an important problem from the standpoint of medical treatmentto create a more superior AVP receptor antagonist and to create an AVPreceptor antagonist free from side effects based on the inhibition ofthe drug metabolizing enzyme CYP.

DISCLOSURE OF THE INVENTION

[0011] The present inventors further made extensive and intensiveinvestigations with respect to compounds having an antagonism againstthe AVP receptor. As a result, it has been found that a novel1,4,5,6-tetrahydroimidazo[4,5-d]benzazepine derivative of the inventionhas a superior antagonism against the AVP receptor and has a lowerinhibition activity against the drug metabolizing enzyme CYP3A4, leadingto accomplishment of the invention.

[0012] Specifically, according to the invention, there is provided anovel 1,4,5,6-tetrahydroimidazo[4,5-d]benzazepine derivative representedby the following general formula (I) or a pharmaceutically acceptablesalt thereof, which is useful as an AVP receptor antagonist.

[0013] (In the formula, the ring D represents phenylene or pyridinediyl;X and Y may be the same or different and each represents CH or N; andR¹, R² and R³ may be the same or different and each represents ahydrogen atom, a hydroxyl group, a halogen, or a lower alkyl,hereinafter the same.)

[0014] Compounds represented by the foregoing general formula (I),wherein the ring D represents 1,4-phenylene, pyridine-2,5-diyl, orpyridine-3,6-diyl, or pharmaceutically acceptable salts thereof arepreferable. Compounds represented by the foregoing general formula (I),wherein the ring D represents 1,4-phenylene, pyridine-2,5-diyl, orpyridine-3,6-diyl; X and Y each represents CH; and R¹ represents ahydrogen atom, or pharmaceutically acceptable salts thereof are morepreferable. Compounds represented by the foregoing general formula (I),wherein the ring D represents 1,4-phenylene; X and Y each represents CH;R¹ represents a hydrogen atom; and R² and R³ each represents a hydrogenatom, or pharmaceutically acceptable salts thereof are the mostpreferable.

[0015] Particularly preferred examples of the compounds include:

[0016]N-{4-[2-(2-pyridyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine-6-carbonyl]phenyl}biphenyl-2-carboxamide,

[0017]N-{3-fluoro-4-[2-(2-pyridyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine-6-carbonyl]phenyl}biphenyl-2-carboxamide,

[0018]2′-fluoro-N-{4-[2-(2-pyridyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine-6-carbonyl]phenyl}biphenyl-2-carboxamide,

[0019]N-{5-[2-(2-pyridyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine-6-carbonyl]-2-pyridyl}biphenyl-2-carboxamide,

[0020]N-{6-[2-(2-pyridyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine-6-carbonyl]-3-pyridyl}biphenyl-2-carboxamide,

[0021]N-{2-hydroxy-4-[2-(2-pyridyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine-6-carbonyl]phenyl}biphenyl-2-carboxamide,and

[0022] pharmaceutically acceptable salts thereof.

[0023] The 1,4,5,6-tetrahydroimidazo[4,5-d]benzazepine derivative havingan antagonism against the AVP receptor according to the invention isstructurally characterized in that a 6-membered aromatic ring havingnitrogen at the 2-position thereof is substituted at the 2-position ofthe imidazobenzazepine ring. Such a structural characteristic achieves areduction of the affinity with the drug metabolizing enzyme CYP3A4.

[0024] Further, according to the invention, there is provided apharmaceutical composition comprising, as an active ingredient, a1,4,5,6-tetrahydroimidazo[4,5-d]benzazepine derivative represented bythe foregoing general formula (I) or a pharmaceutically acceptable saltthereof. Concretely, the invention provides a pharmaceutical compositionas an arginine vasopressin receptor antagonist, which comprises, as anactive ingredient, a 1,4,5,6-tetrahydroimidazo[4,5-d]benzazepinederivative represented by the foregoing general formula (I) or apharmaceutically acceptable salt thereof.

[0025] Moreover, according to the invention, there is provided atherapeutic drug for heart failure or a therapeutic drug forhyponatremia, which comprises, as an active ingredient, a

[0026] 1,4,5,6-tetrahydroimidazo[4,5-d]benzazepine derivativerepresented by the foregoing general formula (I); a compound representedby the foregoing general formula (I), wherein the ring D represents1,4-phenylene, pyridine-2,5-diyl, or pyridine-3,6-diyl; a compoundrepresented by the foregoing general formula (I), wherein the ring Drepresents 1,4-phenylene, pyridine-2,5-diyl, or pyridine-3,6-diyl, X andY each represents CH, and R¹ represents a hydrogen atom; a compoundrepresented by the foregoing general formula (I), wherein the ring Drepresents 1,4-phenylene, X and Y each represents CH, R¹ represents ahydrogen atom, and R² and R³ each represents a hydrogen atom;

[0027]N-{4-[2-(2-pyridyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine-6-carbonyl]phenyl}biphenyl-2-carboxamide;

[0028]N-[3-fluoro-4-[2-(2-pyridyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine-6-carbonyl]phenyl]biphenyl-2-carboxamide;

[0029]2′-fluoro-N-{4-[2-(2-pyridyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine-6-carbonyl]phenyl}biphenyl-2-carboxamide;

[0030]N-{5-[2-(2-pyridyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine-6-carbonyl]-2-pyridyl}biphenyl-2-carboxamide;

[0031]N-{6-[2-(2-pyridyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine-6-carbonyl]-3-pyridyl}biphenyl-2-carboxamide;

[0032]N-{2-hydroxy-4-[2-(2-pyridyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine-6-carbonyl]phenyl}biphenyl-2-carboxamide;or a pharmaceutically acceptable salt thereof.

[0033] The compounds of the invention will be further described below.

[0034] In this description, the term “lower alkyl” means a linear orbranched carbon chain having from 1 to 6 carbon atoms (C₁₋₆), andspecific examples include methyl, ethyl, propyl, isopropyl, butyl,tert-butyl, pentyl, neopentyl, and hexyl. Of these are preferable C₁₋₃alkyls including methyl, ethyl and isopropyl, with methyl and ethylbeing particularly preferred.

[0035] Examples of the “halogen” include a fluorine atom, a chlorineatom, a bromine atom, and an iodine atom.

[0036] Each of the foregoing substituents R¹, R² and R³ may be bound toany position of each ring, but it is desired that R³ is bound to theortho- or para-position.

[0037] The compounds represented by the general formula (I) may possiblyhave an asymmetric carbon atom depending on the kind of thesubstituent(s), and optical isomers may be present based on this. Theinvention includes all of mixtures or isolated compounds of theseoptical isomers.

[0038] Further, with respect to the compounds of the invention, positionisomers based on the imidazole fused on the benzazepine ring may beconsidered. The invention includes all of mixtures or isolated compoundsof these position isomers.

[0039] Moreover, the compounds of the invention may possibly form anacid-addition salt. The invention includes such a salt so far as theyare a pharmaceutically acceptable salt. Specifically, examples includeacid addition salts of an inorganic acid such as hydrochloric acid,hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, andphosphoric acid; and acid addition salts of an organic acid such asformic acid, acetic acid, propionic acid, oxalic acid, malonic acid,succinic acid, fumaric acid, maleic acid, lactic acid, malic acid,tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, aspartic acid, and glutamic acid. In addition,the invention includes various hydrates, solvates and crystalpolymorphisms of the compound of the invention and its pharmaceuticallyacceptable salt. Incidentally, the compound of the invention includesall of so-called prodrugs, i.e., compounds that will be metabolized andconverted into the compound of the foregoing general formula (I) or itssalt within a living body. As the group to form the prodrug according tothe invention are enumerated those groups described in Prog Med., 5,2157-2161 (1985) and Iyakuhin No Kaihatsu (Development of Drugs), Vol.7, “Molecular Design”, 163-198 (1990), by Hirokawa Publishing Co.

[0040] Production Process:

[0041] The compound of the invention and its pharmaceutically acceptablesalt can be produced through application of various known synthesisprocesses by utilizing the characteristic features based on the basicskeleton thereof or kinds of the substituents. Representative productionprocesses will be enumerated below. Incidentally, in some case, it iseffective on the production technology that depending on the kind of afunctional group, the functional group is replaced by a protectivegroup, i.e., a group that can be readily converted into the functionalgroup in the state of the starting materials or intermediates.Thereafter, if desired, the protective group is removed, therebyenabling to obtain the desired compound. Examples of such a functionalgroup include a hydroxyl group and a carboxyl group. Examples of theprotective group thereof include the protective groups as described inGreene and Wuts, Protective Groups in Organic Synthesis (third edition),and these may be properly used depending on the reaction condition.

[0042] Further, as other process, a process in which in a benzyl etherprotected material of a hydroxyl group, pentamethylbenzene is applied ina strongly acidic solution such as trifluoroacetic acid, therebyundergoing deprotection can be enumerated.

[0043] (First Production Process)

[0044] This production process is a process in which an optionallyprotected substituted aromatic carboxylic acid represented by theformula (II) or its reactive derivative and an optionally protectedbenzazepine derivative represented by the formula (III) or its salt aresubjected to amidation in an ordinary manner, and the protectivegroup(s) is removed, if desired, to produce the compound (I) of theinvention.

[0045] Examples of the reactive derivative of the compound (II) includeusual esters such as methyl esters, ethyl esters, and tert-butyl esters;acid halides such as acid chlorides and acid bromides; acid azides;active esters with N-hydroxybenzotriazole, p-nitrophenol,N-hydroxysuccimide, etc.; symmetric acid anhydrides; and mixed acidanhydrides with an alkyl carbonate, p-toluenesufonic acid, etc.

[0046] Further, when the compound (II) is reacted in a liberated acid orreacted without isolating the active ester, it is suitable to use acondensing agent such as dicyclohexylcarbodiimide, carbonyldiimidazole,diphenylphosphoryl azide, diethylphosphoryl cyanide, and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride.

[0047] The reaction varies depending on the reactive derivative and thecondensing agent to be used but is usually carried out in an organicsolvent that is inert to the reaction, such as halogenated hydrocarbonssuch as dichloromethane, dichloroethane, and chloroform, aromatichydrocarbons such as benzene, toluene, xylene, ethers such as ether andtetrahydrofuran, esters such as ethyl acetate, acetonitrile,N,N-dimethylformamide, and dimethyl sulfoxide, under cooling, or at atemperature of from cooling temperature to room temperature, or at atemperature of from room temperature to an elevated temperature.

[0048] Incidentally, in some case, it is advantageous for making thereaction proceed smoothly that the reaction is carried out by using anexcessive amount of the compound (II) or in the presence of a base suchas N-methylmorpholine, trimethylamine, triethylamine,N,N-dimethylaniline, pyridine, 4-(N,N-dimethylamino)pyridine, picoline,and lutidine. Further, a salt comprising a weak base and a strong acid,such as pyridine hydrochloride, pyridine p-toluenesulfonate, andN,N-dimethylaniline hydrochloride, may be used. In the case, theimidazole ring fused with the benzazepine forms a slat together with thestrong acid, and the liberated weak base functions as a catalyst.Pyridine may be used as the solvent.

[0049] Especially, it is suitable to carry out the reaction in a solventsuch as acetonitrile and N,N-dimethylformamide in the presence of a basesuch as pyridine and N,N-dimethylaniline or a salt such as pyridinehydrochloride.

[0050] (Second Production Process)

[0051] (In the formulae, one party of Y¹ and Y², and Y³ and Y⁴represents an oxo group (═O), and the other groups represent a halogenatom and a hydrogen

[0052] The production process is a process in which an optionallyprotected haloketone represented by the formula (IV) and an optionallyprotected amidine represented by the formula (V) or its salt arecyclized in an ordinary manner, and the protective group(s) is removed,if desired, to produce the compound (I) of the invention.

[0053] In this reaction, in some case, the corresponding amidine forms asalt together with an acid. Further, in order to promote the reaction,the reaction may be carried out in the presence of an inorganic basesuch as sodium hydroxide, potassium hydroxide, sodium carbonate,potassium carbonate, sodium hydrogencarbonate, and potassiumhydrogencarbonate, a salt of a weak base and a strong acid, or anorganic base such as pyridine, diisopropylethylamine, and1,5-diazabicyclo[4.3.0]non-5-ene. As the solvent to be used for thereaction, are preferable solvents that are inert to the reaction, suchas alcohols such as methanol, ethanol, and 2-propanol, ethers such asether, tetrahydrofuran, and dioxane, halogenated hydrocarbons such asdichloromethane, chloroform, and carbon tetrachloride, acetonitrile,dimethylformamide, and dimethyl sulfoxide. The reaction temperature ispreferably from room temperature to a refluxing temperature of thesolvent. If desired, the reaction is carried out under an elevatedpressure.

[0054] Incidentally, in this reaction, an oxazole may possibly beformed. In this case, when the reaction is carried out under thecondition of adding ammonium carbonate, ammonium acetate, a formamide,etc. in an ammonia gas stream, the imidazole can be given as a mainproduct.

[0055] The starting compound (IV) that is used for this reaction can beproduced by amidating an optionally protected aromatic carboxylic acid(VI) or its reactive derivative and an optionally protected benzazepine.derivative (VII) or its salt in the same manner as in the firstproduction process and then exerting a halogenating agent, as shown inthe following reaction scheme (if desired, the protective group(s) isremoved at an arbitrary stage). Incidentally, the aromatic carboxylicacid (VI) can be produced by amidating a corresponding, optionallyprotected 2-phenylbenzoic acid (IX) or its reactive derivative and acorresponding, optionally protected amino aromatic carboxylic acid (X)or its salt in the same manner as in the first production process.

[0056] (In the formulae, one party of Y⁵ and Y⁶, and Y⁷ and Y⁸represents an oxo group (═O), and the other party each represents ahydrogen atom

[0057] With respect to the first half amidation, the kind of thereactive derivative and the reaction condition are identical with thoseof the first production process.

[0058] As the halogenating agent that is used in the halogenation step,any halogenating agents that are usually used for halogenation ofsaturated cyclic ketones can be used. Suitable examples include metalreagents such as copper(II) halides such as copper(II) bromide andcopper(II) chloride; and perbromides of pyridine, α-pyrrolidone,quaternary ammonium, dioxane, etc., such as dioxane dibromide,phenyltrimethylammonium tribromide, pyridium hydrobromide perbromide,and pyrrolidone hydrotribromide. Further, single halogen such aschlorine and bromine, or hydrogen halides such as hydrogen chloride andhydrogen bromide can also be used.

[0059] In the reaction using the metal reagent or perbromide, it isusually advantageous to react the compound (VIII) with the halogenatingagent in an organic solvent that is inert to the reaction, such ashalogenated hydrocarbons such as dichloromethane, chloroform, and carbontetrachloride, ethers such as ether, tetrahydrofuran, and dioxane,alcohols such as methanol, ethanol, and 2-propanol, aromatichydrocarbons such as benzene, toluene, and xylene, acetic acid, andethyl acetate, or in water, or in a mixed solvent thereof and in theoptional presence of a small amount of a catalyst such as hydrogenhalides at a temperature of from room temperature to an elevatedtemperature.

[0060] Further, the desired compound can be obtained by reacting thecompound (VIII) with a single halogen as the halogenating agent in asolvent that is inert to the reaction, such as halogenated hydrocarbonssuch as dichloromethane, chloroform, and carbon tetrachloride, ethyleneglycol, and acetic acid, or by reacting the compound (VIII) with ahydrogen halide as the halogenating agent in an acidic solution or abasic solution (such as a sodium hydroxide solution). At this time, thereaction temperature is preferably from −30° C. to the refluxingtemperature of the solvent to be used.

[0061] The thus produced compound of the invention is isolated andpurified as a free form or as a salt after subjecting to salt formationin an ordinary manner. The isolation and purification are carried out byapplying a usual chemical operation such as extraction, concentration,distillation, crystallization, filtration, recrystallization, andvarious kinds of chromatography.

[0062] Various isomers can be isolated in an ordinary manner byutilizing a difference in physicochemical properties among the isomers.For example, in the case of racemic mixtures, the racemic compound canbe introduced into an optically pure isomer by a general racemicresolution method such as a method in which the racemic compound isintroduced into a diastereomer salt with a general optically active acidsuch as tartaric acid, which is then subjected to optical resolution.Further, the mixture of diastereomers can be separated by fractionalcrystallization or various kinds of chromatography. Moreover, it ispossible to produce optically active compounds by using a properoptically active starting material.

Industrial Applicability

[0063] The compound of the invention and its salt have a superiorantagonism against arginine vasopressin V_(1A) and V₂ receptors.

[0064] Accordingly, the compound of the invention has actions of profilebased on such actions, such as water diuresis action, urine eliminatingaction, factor VIII secretion inhibiting action, vasodilation action,cardiac function acceleration action, mesangial cell contractioninhibiting action, mesangial cell proliferation inhibiting action,hepatic gluconeogenesis inhibiting action, platelet aggregationinhibiting action, aldosterone secretion inhibiting action, endoserinproduction inhibiting action, central buffer action, renin secretionregulating action, memory regulating action, body temperature regulatingaction, and prostaglandin production regulating action; is useful as acharacteristic water diuretic, urine eliminant, vasodilator, depressor,drug for heart failure, drug for renal failure, or anticoagulant; and iseffective for prevention and/or therapy of heart failure, hyponatremia,syndrome of inappropriate antidiuretic hormone (SIADH), renal diseases(such as nephrosis, nephritis, diabetic nephropathy, and acute orchronic renal failure), brain edema, ascites, hepatic cirrhosis, etc.

[0065] Further, since the compound of the invention and its salt have anextremely low inhibition action against the drug metabolizing enzymeCYP3A4, they have a low possibility to cause drug interaction with otherdrugs to be metabolized through CYP3A4 as compared with known1,4,5,6-tetrahydroimidazo[4,5-d]benzazepine derivatives. Accordingly,the compound of the invention and its salt are superior from thestandpoint that they can be safely used for combined therapy with otherdrug. Examples of the drugs to be metabolized through CYP3A4 includesimvastatin, lovastatin, fluvastatin, atorvastatin, midazolam,nifedipine, amlodipine, and nicardipine (see SOGORINSHO (OverallClinics), 48(6), 1427-1431, 1999).

[0066] The pharmacological actions of the compound of the invention wereconfirmed by the following assays.

[0067] (1) V_(1A) Receptor Binding Assay:

[0068] A rat hepatic membrane specimen was prepared according to themethod of Nakamura, et al. (Journal of Biological Chemistry, Vol. 258,No. 15, pp. 9283-9289, 1983). The hepatic membrane specimen (30 μg) wasincubated at 25° C. for 60 minutes in a total amount of 250 μL of a 50mM TRIS-HCl buffer solution (pH: 7.4) containing 10 mM magnesiumchloride and 0.1% bovine serum albumin (BSA), together with[³H]-Arg-vasopressin (hereinafter simply referred to as“[³H]-vasopressin”) (0.5 nM, specific activity: 75 Ci/mmol) and a testcompound (from 10⁻¹⁰ to 10⁻⁶ M). Thereafter, liberated [³H]-vasopressinand receptor-binding [³H]-vasopressin were separated from each other byusing a cell harvester, and the receptor-binding [³H]-vasopressin wasadsorbed on a UniFilter plate, GF/B glass filter. After thoroughlydrying, the receptor-binding [³H]-vasopressin was mixed with amicroplate scintillation cocktail, the amount of the receptor-binding[³H]-vasopressin was measured by using TopCount, and an inhibition ratewas calculated according to the following equation.

Inhibition rate (%)=[100−(C ₁ −B ₁)]/(C ₀ −B ₁)×100

[0069] C₁: An amount of [³H]-vasopressin binding to the membranespecimen when treating the receptor membrane specimen in the co-presenceof the test compound having a known concentration and [³H]-vasopressin

[0070] C₀: An amount of [³H]-vasopressin binding to the membranespecimen when treating the receptor membrane specimen in the presence of[³H]-vasopressin and in the absence of the test compound

[0071] B₁: An amount of [³H]-vasopressin binding to the membranespecimen when treating the receptor membrane specimen in the co-presenceof [³H]-vasopressin and an excessive amount of vasopressin (10⁻⁶ M)

[0072] According to the foregoing equation, a concentration of the testcompound at the inhibition rate of 50% (IC₅₀ value) was calculated, fromwhich was then calculated an affinity of the test compound with thereceptor, i.e., a dissociation constant (Ki), according to the followingequation.

Ki=IC₅₀/(1+[L]/Kd)

[0073] [L]: A concentration of [³H]-vasopressin

[0074] Kd: A dissociation constant of [³H]-vasopressin against thereceptor as determined by the saturation binding assay

[0075] A logarithm of the Ki value as calculated according to theforegoing equation was taken, and its negative value was defined as apKi value.

[0076] (2) V₂ Receptor Binding Assay:

[0077] A rat renal medullary membrane specimen was prepared according tothe method of Cambell, et al. (Journal of Biological Chemistry, Vol.247, No. 19, pp. 6167-6175, 1972). The rat renal medullary membranespecimen (200 μg) was treated together with [³H]-vasopressin (0.5 nM,specific activity: 75 Ci/mmol) and a test compound (from 10⁻¹⁰ to 10⁻⁶M) in the same manner as in the foregoing V_(1A) receptor binding assay,and the same measurement was carried out to determine a pKi value.

[0078] (3) Cytochrome P450 (3A4) Inhibition Assay:

[0079] An assay was carried out according to the method of Crespi, etal. (Analytical Biochemistry, 248, 188-190, 1997). Using a 96-wellplate, BFC (5×10⁻⁵ M) as a substrate, a test compound (from 9.1×10⁻⁸ to2×10⁻⁵ M), and an enzyme (10⁻⁸ M) were incubated at 37° C. for 30minutes in a total amount of 100 μL of a 20 mM phosphoric acid buffersolution (pH: 7.4) containing 1.3 mM NADP+, 3.3 mM glucose-6-pharpahte,3.3 mM magnesium chloride, and 0.4 Units/mL glucose-6-phosphatedehydrogenase. Thereafter, a 100 mM TRIS buffer solution containing 80%acetonitrile was added to stop the reaction, and a fluorescent intensity(excitation wavelength: 409 nm, fluorescent wavelength: 530 nm) wasmeasured by a fluorescent plate reader. An inhibition rate wascalculated according to the following equation, and a concentration ofthe test compound at the inhibition rate of 50% (IC₅₀ value) wasdetermined.

Inhibition rate (%)=[100−(C ₁ −B ₁)]/(C ₀ −B ₁)×100

[0080] C₁: A fluorescent intensity in the presence of the test compoundhaving a known concentration, enzyme and the substrate

[0081] C₀: A fluorescent intensity in the presence of enzyme and thesubstrate and in the absence of the test compound

[0082] B₁: A fluorescent intensity of the blank well TABLE 1 Antagonismagainst arginine vasopressin V_(1A) and V₂ receptors and inhibitionaction against drug metabolizing enzyme CYP3A4 Inhibition activityBinding activity Binding activity against drug against arginine againstarginine metabolizing vasopressin V_(1A) vasopressin V₂ enzyme CYP3A4Example No. receptor (pki) receptor (pKi) (IC₅₀/μM)  1 8.55 8.22 7.82  98.42 7.98 2.4 11 8.71 7.91 2.0 12 8.12 7.54 5.9 Control 8.11 8.07 0.21compound 1¹⁾ Control 8.91 8.98 0.43 compound 2²⁾

[0083] As shown in Table 1, it has become clear that the compounds ofthe invention have a superior receptor-binding activity against theV_(1A) receptor and V₂ receptor and a low inhibition activity againstthe drug metabolizing enzyme CYP3A4.

[0084] The drug of the invention can be prepared by a usually employedmethod using one or two or more of the compound of the inventionrepresented by the general formula (I) and a pharmaceutical carrier,excipient and other additives as used for formulation. Theadministration may be in any form of oral administration by tablets,pills, capsules, granules, powders, liquids, etc., or parenteraladministration by injections such as intravenous or intramuscularinjection, suppositories, transnasal administration, transmucousadministration, dermal administration, etc.

[0085] As a solid composition for the oral administration according tothe invention, tablets, powders, or granules are used. In such a solidcomposition, one or more active substances are mixed with at least oneinert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, andmagnesium metasilicate aluminate. The composition may contain additivesother than the inert diluent, such as a lubricant such as magnesiumstearate, a disintegrating agent such as cellulose calcium glycolate, astabilizer such as lactose, and a dissolution aid such as glutamic acidand aspartic acid, according to the customary method. If desired, thetablets or pills may be coated by a sugar coating such as sugar,gelatin, hydroxypropyl cellulose, and hydroxypropylmethyl cellulosephthalate, or a film made of a gastric-soluble or intestinal solublesubstance.

[0086] The liquid composition for oral administration contains apharmaceutically acceptable emulsion agent, solution agent, suspendingagent, syrup, or elixir and contains a generally employed inert diluentsuch as purified water and ethanol. In addition to the inert diluent,this composition may contain an auxiliary agent such as a wetting agentand a suspending agent, a sweetener, a flavor, an aromatic, or anantiseptic.

[0087] The injection for parenteral administration contains a sterileaqueous or non-aqueous solution agent, suspending agent or emulsionagent. Examples of the aqueous solution agent or suspending agentinclude distilled water or physiological saline for injection. Examplesof the non-aqueous solution agent or suspending agent include propyleneglycol, polyethylene glycol, vegetable oils such as olive oil, alcoholssuch as ethanol, and Polysolvate 80. Such a composition may also containan auxiliary agent such as an antiseptic, a wetting agent, anemulsifier, a dispersing agent, a stabilizer such as lactose, and adissolution aid such as glutamic acid and aspartic acid. Thesecompositions are sterilized by, for example, filtration through abacteria-holding filter, compounding with an anti-bacterial agent, orirradiation. Further, these can be used by producing a sterile solidcomposition and dissolving it in sterile water or a sterile solvent forinjection before the use.

[0088] Concretely, for example, 1.0 mg of the compound of Example 6, 300mg of propylene glycol, and 100 mg of ethanol are mixed, to which isthen added water for injection to make a total volume of 1 mL, wherebythe injection can be prepared.

[0089] Usually, in the case of the oral administration, it is properthat the dose of the drug per day is from about 0.0001 to 50 mg per kg,preferably from about 0.001 to 10 mg per kg, and more preferably from0.01 to 1 mg per kg of the body weight and that the drug is administeredonce or dividedly two to four times. In the case of the intravenousadministration, it is proper that the dose of the drug per day is fromabout 0.0001 to 1 mg per kg, and preferably from about 0.0001 to 0.1 mgper kg of the body weight and that the drug is administered once ordividedly several times. The dose is properly determined depending onthe individuals while taking into consideration the symptom, age andsex.

BEST MODE FOR CARRYING OUT THE INVENTION

[0090] The invention will be specifically described below with referenceto the following Examples, but it should not be limited thereto.Incidentally, the production processes of the starting compounds to beused in the following Examples will be described with reference to theReferential Examples.

EXAMPLE 1

[0091]N-{4-[2-(2-Pyridyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine-6-carbonyl]phenyl}biphenyl-2-carboxamidehydrochloride

[0092] In 30 mL of tetrahydrofuran was dissolved in 1.0 g ofN-[4-(5-oxo-2,3,4,5-tetrahydro-1H-benzazepine-1-carbonyl)phenyl]biphenyl-2-carboxamide,to which was then added 0.902 g of phenyltrimethylammonium tribromide,and the mixture was stirred at room temperature for 150 minutes. Aninsoluble matter of the reaction mixture was removed by filtration, andthe solvent was distilled off in vacuo. The resulting residue wasdissolved in 30 mL of chloroform, to which were then added 1.70 g of2-amidinopyridinium hydrochloride hydrate and 2.1 g of potassiumcarbonate, and the mixture was refluxed upon heating for 9 hours. Thereaction mixture was cooled and rinsed with water, and the chloroformlayer was dried over anhydrous magnesium sulfate. The solvent wasdistilled off, and the resulting residue was subjected to silica gelchromatography and eluted with chloroform-methanol (70:1). To the eluatewas added 0.9 mL of a 4M hydrochloric acid-ethyl acetate solution inchloroform, and the solvent was then distilled off. The resultingresidue was recrystallized from acetonitrile to obtain 0.830 g of thetitled compound.

[0093] Compounds of Examples 2 to 4 as shown in Table 2 were produced inthe same manner as in Example 1 while using the respective correspondingstarting materials.

[0094] Incidentally, the abbreviations shown below are used in the table(hereinafter the same).

[0095] Ex: Example No., Ref: Referential Example No., salt: salt (nodescription: free form, HCl: hydrochloride, H₂O: hydrate), Data:Physicochemical data, MS: FAB-MS(M+H)⁺, MS-: FAB-MS(M−H)⁻, NMR: ¹H-NMR δ(ppm), m.p.: Melting point (° C.) TABLE 2

Ex R salt Data 1

HCl NMR(DMSO-d₆); 3.00-3.15(1H,m), 3.21-3.40(2H,m), 4.95-5.10 (1H,m),6.87(1H,d,J=6.8Hz), 6.99(2H,d,J=7.8Hz), 7.18(1H,t,J=7.8Hz),7.24-7.57(12H,m), 7.70(1H,dd,J=4.6Hz,7.3Hz), 8.19(1H, dt,J=1.4Hz,7.8Hz),8.45(1H,d,J=7.3Hz), 8.81(1H,d,J=7.8Hz), 8.86(1H,d,J=4.6Hz), 10.31(1H,s).MS; 562. 2

HCl NMR(DMSO-d₆); 2.98-3.10(1H,m), 3.12-3.34(2H,m), 4.93-5.08 (1H,m),6.79(1H,d,J=7.3Hz), 6.92(2H,d,J=8.0HZ), 7.02(1 H,d,J=8.0Hz),7.23-7.60(12H,m), 8.33(1H,d,J=8.0Hz), 8.75(1H,d,J=2.2 Hz),8.77-8.81(1H,m), 9.56(1H,s), 10.28(1H,s). MS; 563. 3

HCl NMR(DMSO-d₆); 2.66(3H,s), 3.00-3.15(1H,m), 3.20-3.37(2H, m),4.95-5.10(1H,m), 6.85(1H,d,J=7.3Hz), 6.97(2H,d,J=8.1Hz),7.15(1H,t,J=8.1Hz), 7.25-7.58(13H,m), 8.04(1H,t,J=8.1Hz), 8.37(1H,d,J=8.1Hz), 8.47(1H,d,J=7.3Hz), 10.29(1H,s). MS-; 574. 4

HCl NMR(DMSO-d₆); 3.00-3.12(1H,m), 3.15-3.36(2H,m), 4.95-5.06 (1H,m),6.83(1H,d,J=7.3Hz), 6.95(2H,d,J=7.3Hz), 7.12(1H,t,J=7.3Hz),7.24-7.56(12H,m), 7.70(1H,t,J=5.1Hz), 8.29(1H,dd,J=1.4 Hz, 8.1Hz),9.08(2H,d,J=5.1Hz), 10.29(1H,s). MS; 563.

Referential Example 1

[0096]2-(2-Pyridyl)-1,4,5,6-tetrahydro-6-(4-methylbenzenesulfonyl)imidazo[4,5-d][1]benzazepine

[0097] In 30 mL of chloroform was dissolved 2.0 g of1,2,3,4-tetrahydro-1-(4-methylbenzenesulfonyl)-1-benzazepin-5-one, towhich was then added dropwise a solution of 0.33 mL of bromine in 10 mLof chloroform. The mixture was stirred at room temperature for one hour.The reaction mixture was rinsed with saturated sodium hydrogencarbonateand then dried over anhydrous sodium sulfate. The solvent was distilledoff, and the resulting residue was dissolved in 30 mL of chloroform. Tothe solution were added 5.0 g of 2-amidinopyridinium hydrochloridehydrate and 5.3 g of potassium carbonate, and the mixture was refluxedupon heating for 10 hours. The reaction mixture was cooled, and thesolvent was then distilled off. To the resulting residue was added 30 mLof a 1M hydrochloric acid aqueous solution, and a deposited solid wascollected by filtration. The resulting solid was suspended in chloroformand rinsed with a 1M sodium hydroxide aqueous solution, and thechloroform layer was dried over anhydrous magnesium sulfate. The solventwas distilled off, and the resulting residue was recrystallized fromethanol to obtain 1.70 g of the titled compound.

[0098]¹H-NMR (DMSO-d₆): δ2.12 (3H, s), 3.00 to 3.33 (4H, br), 7.13 (2H,d, J=8.1 Hz), 7.21 (1H, dt, J=1.4 Hz, 8.1 Hz), 7.29 to 7.43 (5H, m),7.89 (1H, dt, J=1.4 Hz, 8.1 Hz), 8.07 (1H, d, J=8.1 Hz), 8.17 (1H, d,J=7.3 Hz), 8.60 (1H, d, J=4.4 Hz)

Referential Example 2

[0099] 2-(2-Pyridyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine

[0100] In 9 mL of sulfuric acid and 4.3 mL of acetic acid was dissolved2.93 g of the compound of Referential Example 1, and the solution wasstirred upon heating on a water bath at 70° C. for 90 minutes. Thereaction mixture was poured into 100 mL of ice water, to which was thenadded a 10M sodium hydroxide aqueous solution to make the mixture basic.After further adding 200 mL of methyl ethyl ketone, the mixture wassubjected to liquid-liquid separation. The organic layer was rinsed withsaturated salt water and then dried over anhydrous sodium sulfate. Thesolvent was distilled off, and the resulting residue was crystallizedfrom ethyl acetate. A deposited crystal was collected by filtration anddried to obtain 1.038 g of the titled compound.

[0101]¹H-NMR (DMSO-d₆): δ2.97 (2H, t, J=5.1 Hz), 3.20 to 3.26 (2H, m),5.95 (1H, t, J=3.7 Hz), 6.73 to 6.82 (2H, m), 6.93 (1H, dt, J=1.5 Hz,7.3 Hz), 7.34 (1H, dd, J=4.4 Hz, 8.1 Hz), 7.86 (1H, dt, J=1.5 Hz, 8.1Hz), 8.11 (1H, d, J=8.1 Hz), 8.24 (1H, dd, J=1.5 Hz, 8.1 Hz), 8.59 (1H,d, J=4.4 Hz), 12.67 (1H, s)

Referential Example 3

[0102] Methyl 4-[(biphenyl-2-carbonyl)amino]-2-fluorobenzoate

[0103] To a solution of 0.66 g of 2-phenylbenzoic acid, 7 mL oftetrahydrofuran, and one drop of N,N-dimethylformamide was added 0.29 mLof thionyl chloride under ice cooling, and the reaction mixture wasstirred at room temperature for 2 hours. The reaction mixture wasconcentrated in vacuo, 3 mL of toluene was added to the residue, and themixture was again concentrated in vacuo. The resulting residue wasdissolved in 3 mL of chloroform, and the solution was added dropwise toa chloroform solution (6 mL) containing 0.56 g of methyl4-amino-2-fluorobenzoate and 0.63 mL of dimethylaniline under icecooling. The mixture was stirred at room temperature for 4 hours. Thereaction mixture was diluted with ethyl acetate, and the organic layerwas rinsed with a 1M hydrochloric acid aqueous solution and a 1M sodiumhydroxide aqueous solution. The organic layer was dried over anhydroussodium sulfate, and the solvent was then distilled off in vacuo. Theresulting residue was subjected to silica gel chromatography and elutedwith hexane-thyl acetate (3:1) to obtain 1.00 g of the titled compound.

[0104] Compounds of Referential Examples 4 to 7 as shown in Table 3 wereproduced in the same manner as in Referential Example 3 while using therespective corresponding starting materials. TABLE 3

Ref R³ D R′ Data 3 H

Me NMR(CDCl₃); 3.88(3H,s), 6.64(1H,d,J=8.4Hz), 7.01-7.13(1H,m),7.40-7.61(8H,m), 7.72-7.80(1H,m), 7.87-7.94(1H,m). 4 H

Me NMR(CDCl₃); 3.86(3H,s), 7.91(2H,s), 7.18-7.54(13H, m),7.63-7.68(1H,m), 7.80(1H,dd,J=1.7Hz,7.5Hz), 7.86(1H,s),8.59(1H,d,J=8.4Hz). 5 2-F

Et NMR(CDCl₃); 1.37(3H,t,J=7.1Hz), 4.33(2H,q,J=7.1 Hz),7.11(1H,ddd,J=1.1Hz,8.0Hz,9.5Hz), 7.22(1H, dd,J=1.1Hz,7.5Hz),7.28-7.45(5H,m), 7.52-7.58(2H,m). 6 H

Me NMR(CDCl₃); 3.90(3H,s), 6.81(1H,d,J=7.9Hz), 7.05-7.13(1H,m),7.18-7.59(4H,m), 7.83(1H,m),8.21(1H, ddd,J=2.0Hz,8.8Hz,11.2Hz),8.25-8.33(2H,m), 8.64-8.67(1H,m), 8.77(1H,d,J=2.0Hz). 7 H

Me NMR(CDCl₃); 3.95(3H,s), 7.24-7.71(9H,m), 7.88-7.94 (1H,m),8.04(1H,d,J=8.6Hz), 8.53-8.58(1H,m).

Referential Example 8

[0105] 4-[(Biphenyl-2-carbonyl)amino]-2-fluorobenzoic acid

[0106] In 10 mL of ethanol was dissolved 1.00 g of the compound ofReferential Example 3, to which was then added 4.35 mL of a 1M sodiumhydroxide aqueous solution. The reaction mixture was stirred at roomtemperature for 2 days. A 1M hydrochloric acid aqueous solution wasadded to the reaction mixture to make it have a pH of 6, and a depositedsolid was collected by filtration. The resulting solid wasrecrystallized from ethyl acetate to obtain 0.77 g of the titledcompound.

[0107] Compounds of Referential Examples 9 to 12 as shown in Table 4were produced in the same manner as in Referential Example 8 while usingthe respective corresponding starting materials. TABLE 4 Ref R³ D Data 8H

m.p.:233-235° C. 9 H

m.p.:162-164° C. 10 2-F

m.p.:219-222° C. 11 H

m.p.:86-89° C. 12 H

m.p.113-116° C.

EXAMPLE 5

[0108]N-{4-[2-(2-Pyridyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine-6-carbonyl]phenyl}biphenyl-2-carboxamidemonohydrate

[0109] To a suspension of 3.60 g of4-[(biphenyl-2-carbonyl)amino]benzoic acid, 100 mL of tetrahydrofuran,and one drop of N,N-dimethylformamide was added 1.21 mL of thionylchloride under ice cooling, and the reaction mixture was stirred at roomtemperature for 2 hours 30 minutes. The reaction mixture wasconcentrated in vacuo, 5 mL of toluene was added to the residue, and themixture was again concentrated in vacuo. To the resulting residue wasadded an acetonitrile solution (90 mL) of 2.84 g of the compound ofReferential Example 2, and the mixture was stirred upon heating on awater bath at 80° C. for 17 hours 30 minutes. The reaction mixture wascooled to room temperature, and a deposited precipitate was collected byfiltration and rinsed with acetonitrile. The resulting solid wassuspended in a 1M sodium hydroxide aqueous solution and then extractedwith chloroform. The chloroform layer was dried over anhydrous sodiumsulfate, and the solvent was distilled off in vacuo. The resultingresidue was crystallized from ethyl acetate to obtain 4.921 g of thetitled compound.

[0110]¹H-NMR (DMSO-d₆): δ2.61 to 3.30 (3H, m), 4.93 to 5.40 (1H, m),6.72 (1H, d, J=7.3 Hz), 6.88 (2H, d, J=7.8 Hz), 6.96 (1H, t, J=7.8 Hz),7.24 to 7.56 (13H, m), 7.94 (1H, dt, J=2.0 Hz, 7.8 Hz), 8.19 (1H, d,J=7.8 Hz), 8.29 (1H, d, J=7.3 Hz), 8.65 (1H, d, J=4.4 Hz), 10.28 (1H,s), 13.05 (1H, s) FAB-MS(M+H)⁺: 562 Elemental analysis asC₃₆H₂₇N₅O₂.H₂O: (Calculated): C: 74.59%, H: 5.04%, N: 12.08%, O: 8.28%(Found): C: 74.89%, H: 5.01%, N: 12.15%

EXAMPLE 6

[0111]N-{4-[2-(2-Pyridyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine-6-carbonyl]phenyl}biphenyl-2-carboxamide

[0112] To 1.0 g of the compound of Example 5 was added 20 mL ofacetonitrile, and the mixture was stirred upon heating on an oil bath at95° C. for 35 minutes. The suspension was cooled to room temperature,and a precipitate was collected by filtration and rinsed with 6 mL ofacetonitrile to obtain 0.85 g of the titled compound.

[0113]¹H-NMR (DMSO-d₆): δ2.97 to 3.26 (3H, m), 4.97 to 5.00 (1H, m),6.71 (1H, d, J=7.6 Hz), 6.88 (2H, d, J=8.4 Hz), 6.95 (1H, t, J=7.6 Hz),7.24 to 7.57 (13H, m), 7.94 (1H, dt, J=1.6 Hz, 7.6 Hz), 8.18 (1H, d,J=7.6 Hz), 8.30 (1H, d, J=8.0 Hz), 8.63 (1H, d, J=4.8 Hz), 10.27 (1H,s), 13.03 (1H, s) FAB-MS(M+H)⁺: 562 Melting point: 240 to 242° C.Elemental analysis as C₃₆H₂₇N₅O₂ (Calculated): C: 76.99%, H: 4.85%, N:12.47%, O: 5.70% (Found): C: 77.08%, H: 4.93%, N: 12.39%

EXAMPLE 7

[0114]N-{4-[2-(2-Pyridyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine-6-carbonyl]phenyl}biphenyl-2-carboxamidehydrochloride

[0115] To a suspension of 0.605 g of4-[(biphenyl-2-carbonyl)amino]benzoic acid, 10 mL of tetrahydrofuran,and one drop of N,N-dimethylformamide was added 0.167 mL of ice-cooledthionly chloride, and the reaction mixture was stirred at roomtemperature for 4 hours. The reaction mixture was concentrated in vacuo,5 mL of toluene was added to the residue, and the mixture was againconcentrated in vacuo. To the resulting residue was added anacetonitrile solution (25 mL) of 0.385 g of the compound of ReferentialExample 2, and the mixture was stirred upon heating on a water bath at80° C. for 4 hours. The reaction mixture was cooled to room temperature,and a deposited precipitate was collected by filtration and rinsed withacetonitrile. The resulting solid was suspended in a 1M sodium hydroxideaqueous solution and extracted with chloroform. The chloroform layer wasdried over anhydrous sodium sulfate, and the solvent was distilled offin vacuo. The resulting residue was subjected to silica gel columnchromatography and eluted with chloroform-methanol (49:1). The eluatewas concentrated in vacuo, and the resulting residue was crystallizedfrom ethyl acetate to obtain 0.566 g ofN-{4-[2-(2-pyridyl)-1,4,5,6-tetrahydro-imidazo[4,5-d][1]benzazepine-6-carbonyl]phenyl}biphenyl-2-carboxamide.The resulting crystal was suspended in an ethyl acetate-methanol mixedsolution, to which was then added 0.277 mL of a 4M hydrochloricacid-ethyl acetate solution, and the solvent was distilled off in vacuo.The resulting residue was suspended in 20 mL of ethanol, and thesuspension was stirred upon heating on a water bath at 80° C. for 10minutes. The suspension was cooled to room temperature, and aprecipitate was collected by filtration and rinsed with ethanol toobtain 0.350 g of the titled compound.

[0116] The physicochemical data of Example 7 were identical with thoseof Example 1.

[0117] Compounds of Examples 8 to 11 and a compound of ReferentialExample 13 as shown in Table 5 were produced in the same manner as inExample 7 while using the respective corresponding starting materials.

EXAMPLE 12

[0118]N-{2-Hydroxy-4-[2-(2-pyridyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]-benzazepine-6-carbonyl]phenyl}biphenyl-2-carboxamidehydrochloride

[0119] In 6 mL of trilfuoroacetic acid was dissolved 0.525 g of thecompound of Referential Example 13, to which was then added 0.466 g ofpentamethylbenzne. The reaction mixture was stirred at room temperaturefor 3 hours, and 0.233 g of pentamethylbenzene was further added to thereaction mixture. The reaction mixture was stirred at room temperaturefor an additional 21 hours. The reaction mixture was concentrated invacuo, 3 mL of toluene was added to the residue, and the mixture wasagain concentrated in vacuo. The resulting residue was dissolved in 10mL of chloroform, to which was then added 10 mL of a 1M sodium hydroxideaqueous solution, and a deposited solid was collected by filtration. Tothe resulting solid was added 0.20 mL of a 4M hydrochloric acid-ethylacetate solution, and the solvent was distilled off. The resultingresidue was recrystallized from ethanol to obtain 0.300 g of the titledcompound. TABLE 5

R³ D salt Data Ex 8 H

HCl NMR(DMSO-d₆); 3.08-3.28(2H,m), 3.30-3.42(1H, m), 4.88-4.98(1H,m),6.92(1H,d,J=8.1Hz), 7.08-7.18(2H,m), 7.25(1H,d,J=8.0Hz), 7.28-7.40(7H,m), 7.47(2H,t,J=8.1Hz), 7.54-7.60(2H,m), 7.63-7.68 (1H,m),8.15(1H,t,J=6.6Hz), 8.33(1H,d,J=8.0Hz), 8.60(1H,d,J=7.3Hz),8.82(1H,d,J=4.4Hz), 10.45 (1H,s). MS; 580. Ex 9 2-F

HCl NMR(DMSO-d₆); 2.97-3.14(1H,m), 3.18-3.40(2H, m), 4.90-5.11(1H,m),6.86(1H,d,J=7.3Hz), 6.98 (2H,d,J=7.3Hz), 7.10-7.21(3H,m), 7.28-7.43(6H,m), 7.48-7.68(4H,m), 8.16(1H,t,J=7.3Hz), 8.42(1H, d,J=8.1Hz),8.73(1H,d,J=7.3Hz), 8.83(1H,d,J=4.4Hz), 10.36(1H,s). MS; 580. Ex 10 H

HCl NMR(DMSO-d₆); 3.05-3.18(1H,m), 319-3.40(2H, m), 4.93-5.08(1H,m),6.96(1H,d,J=8.0Hz), 7.19 (1H,t,J=7.4Hz), 7.24-7.57(11H,m),7.61(1H,dd,J=7.1Hz,7.3Hz), 7.74-7.82(1H,m), 7.83-7.89(1H, m),8.15(1H,dt,J=1.6Hz,8.0Hz), 8.40(1H,d,J=8.0 Hz), 8.58-8.68(1H,m),8.81(1H,d,J=4.4Hz), 10.75 (1H,s). MS; 563. Ex 11 H

HCl NMR(DMSO-d₆); 3.10(1H,dt,J=2.9Hz, 13.2Hz), 3.02-3.40(2H,m),4.98(1H,dd,J=5.2Hz, 13.2Hz), 6.77(1H,d,J=8.0Hz), 7.09(1H,t,J=7.3Hz),7.24-7.69 (13H,m), 7.90(1H,dd,J=2.2Hz,8.8Hz), 8.14(1H, t,J=7.3Hz),8.30(1H,d,J=7.3Hz), 8.56(1H,d,J=8.1Hz), 8.81(1H,d,J=4.4Hz), 10.47(1H,s).MS; 563. Ref 13 H

NMR(DMSO-d₆); 2.96-3.20(3H,m), 4.87-4.99 (1H,m), 6.34(1H,brs),6.65-6.78(2H,m), 6.94-7.02 (1H,m), 7.08-7.50(15H,m), 7.55(1H,t,J=7.0Hz),7.64-7.71(1H,m), 7.94(1H,dt,J=1.7Hz,7.7Hz), 8.23 (1H,d,J=8.1Hz),8.31(1H,s), 8.35-8.41(1H,m),8.65-8.72(1H,m), 9.06(1H,brs),13.06(1H,brs). Ex 12 H

HCl NMR(DMSO-d₆); 2.98-3.10(1H,m), 3.17-3.25 (2H,m), 4.90-5.08(1H,m),6.34(1H,d,J=5.9Hz), 6.76 (1H,s), 6.82-6.90(1H,m), 7.15(1H,t,J=7.3Hz),7.26-7.49(8H,m), 7.53-7.59(2H,m), 7.65(1H,dd,J=5.1 Hz,7.3Hz),8.15(1H,t,J=8.8Hz), 8.50(1H,d,J=8.1 Hz), 8.75-8.85(2H,m), 9.13(1H,s),10.00(1H,s). MS; 578.

[0120] Structures of other compounds of the invention will be shown inTables 6 to 8. These compounds can be easily synthesized in theforegoing production processes or the processes as described in theExamples, or by undergoing slight modifications within the range obviousto those skilled in the art.

[0121] Incidentally, the term “No” in the tables means a compoundnumber. TABLE 6

No X Y R¹¹ R¹² P Q R³¹ R³² A1  CH N H H CH CH F H A2  CH N H H CF CH H HA3  CH N H H N CH H H A4  CH N H H CH N H H A6  CH N H H CH C(OH) H HA6  N CH H H CH CH F H A7  N CH H H CF CH H H A8  N CH H H N CH H H A9 N CH H H CH N H H A10 N CH H H CH C(OH) H H A11 CH CH CH₃ H CH CH F HA12 CH CH CH₃ H CF CH H H A13 CH CH CH₃ H N CH H H A14 CH CH CH₃ H CH NH H A15 CH CH CH₃ H CH C(OH) H H A16 CH CH H H CH CH Cl H A17 CH CH H HCH CH H Cl A18 CH CH H H CH CH OH H A19 CH CH H H CH CH H OH A20 CH CHCl H CH CH H H A21 CH CH H CH₃ CH CH H H

[0122] TABLE 7

No. X Y R¹¹ P Q R T R³¹ A22 CH CH H CH CH CH CH F A23 CH CH H CH CH CHCH H A24 CH CH H N CH CH CH H A25 CH CH H CH N CH CH H A26 CH CH H CH CHN CH H A27 CH CH H CH CH CH N H A28 CH CH H CF CH CH CH H A29 N CH H CHCH CH CH H A30 CH N H CH CH CH CH H A31 CH CH CH₃ CH CH CH CH H

[0123] TABLE 8

No X Y R¹¹ P Q R T R+HU,31 A32 CH CH H CH CH CH CH F A33 CH CH H CH CHCH CH H A34 CH CH H N CH CH CH H A35 CH CH H CH N CH CH H A36 CH CH H CHCH N CH H A37 CH CH H CH CH CH N H A38 CH CH H CF CH CH CH H A39 N CH HCH CH CH CH H A40 CH N H CH CH CH CH H A41 CH CH CH₃ CH CH CH CH H

1. A 1,4,5,6-tetrahydroimidazo[4,5-d]benzazepine derivative representedby the following general formula (I) or a pharmaceutically acceptablesalt thereof:

wherein the ring D represents phenylene or pyridinediyl; X and Y may bethe same or different and each represents CH or N; and R¹, R² and R³ maybe the same or different and each represents a hydrogen atom, a hydroxylgroup, a halogen, or a lower alkyl.
 2. The compound or itspharmaceutically acceptable salt according to claim 1, wherein the ringD represents 1,4-phenylene, pyridine-2,5-diyl, or pyridine-3,6-diyl. 3.The compound or its pharmaceutically acceptable salt according to claim2, wherein X and Y each represents CH, and R¹ represents a hydrogenatom.
 4. The compound or its pharmaceutically acceptable salt accordingto claim 3, wherein the ring D represents 1,4-phenylene, and R² and R³each represents a hydrogen atom.
 5. The compound or its pharmaceuticallyacceptable salt according to claim 1, wherein the compound isN-{4-[2-(2-pyridyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine-6-carbonyl]phenyl}biphenyl-2-carboxamide,N-{3-fluoro-4-[2-(2-pyridyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine-6-carbonyl]phenyl}biphenyl-2-carboxamide,2′-fluoro-N-{4-[2-(2-pyridyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine-6-carbonyl]phenyl}biphenyl-2-carboxamide,N-{5-[2-(2-pyridyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine-6-carbonyl]-2-pyridyl}biphenyl-2-carboxamide,N-{6-[2-(2-pyridyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine-6-carbonyl]-3-pyridyl}biphenyl-2-carboxamide, orN-{2-hydroxy-4-[2-(2-pyridyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine-6-carbonyl]phenyl}biphenyl-2-carboxamide.6. A pharmaceutical composition comprising, as an active ingredient, a1,4,5,6-tetrahydroimidazo[4,5-d]benzazepine derivative represented bythe general formula (I) or a pharmaceutically acceptable salt thereof.7. The pharmaceutical composition as claimed in claim 6, which is anarginine vasopressin receptor antagonist.
 8. A pharmaceuticalcomposition for therapy for heart failure or therapy for hyponatremia,which comprises, as an active ingredient, the compound or itspharmaceutically acceptable salt according to any one of claims 1 to 5.